Simultaneous dual-isotope SPECT allows imaging of two physiological processes under identical conditions, thereby expanding the possibilities for clinical diagnosis, as well as fundamental investigation. The goal of the proposed research is to optimize, using task-specific metrics, the acquisition and processing of simultaneous Tc-99m and I-123 brain and cardiac studies, as well as Tc-99m and TI-201 cardiac studies. We will determine theoretical bounds on performance in several clinically relevant estimation tasks for both simultaneous and sequential dual-energy SPECT imaging, for several values of energy resolution, and for PET imaging. We will develop a comprehensive strategy, based on energy spectral methods and iterative reconstruction, for quantitative simultaneous Tc-99m/l-123 brain and cardiac SPECT. Our experience in dual isotope SPECT will be extended to simultaneous assessment of dopamine transporters with Tc-99m tracer using dynamic SPECT, and of dopamine receptors with l-123-IBZM. Dynamic and spectral a priori information will be used with artificial neural networks and factor analysis of dynamic sequences to obtain a robust estimate of the primary data sets for both radionuclides. We will develop a multiple-energy joint iterative reconstruction algorithm, using rapid Monte Carlo simulation of lead x-rays, scatter, cross-talk and high-energy contamination in several energy windows, to correct simultaneously for these factors in SPECT imaging of dual isotope pairs (Tc-99m/l-123, Tc-99m/TI-201). We will evaluate the improvements in task performance due to the new processing techniques using Monte Carlo simulations and physical acquisitions, and validate them, by patient studies, in the diagnosis of early idiopathic Parkinson disease (PD) and in the diagnosis of coronary artery disease. We expect that our approach will make quantitative simultaneous dualisotope imaging clinically feasible, and lead to earlier diagnosis and better monitoring of PD and to improved evaluation of suspected acute cardiac ischemia.